Project Summary/Abstract Repetitive and severe seizures in temporal lobe epilepsy patients cause neuropathological changes in the brain, such as neurodegeneration, gliosis, and cell death in the hippocampus, which are associated with cognitive deficits. Studies in rodent models have shown that increasing the extracellular concentration of the neurotransmitter serotonin through Selective Serotonin Reuptake Inhibitors (SSRIs) is capable of reducing seizure severity, preventing neuropathological plasticity in the hippocampus, and precluding associated memory impairments. These findings suggest that serotonin neurons are essential for maintaining normal resistance to seizures and further that augmenting serotonergic neuronal signaling may be able to prevent seizures or seizure-induced impairments. However, little is known about the underlying serotonergic circuitry and responsible serotonin neuronal subtypes, though such discovery could provide a path to more efficient epilepsy treatments. With this motivation, coupled with recent findings by our lab and others identifying in mice functionally and molecularly distinct subtypes of serotonergic neurons, we hypothesize that the three major subtypes of serotonergic neurons that project to the hippocampus do not contribute equally to regulating seizure susceptibility and post-seizure neuropathological changes. To test this, I will employ loss- and gain-of-neuron activity experiments in which individually each of these three hippocampal-projecting subtypes of serotonergic neurons are selectively manipulated in vivo using our labs well-established intersectional genetic tools, but now within the context of a robust kainic acid-induced seizure model. More specifically, in Aim 1, I will assess the effects of serotonergic neuron subtype inhibition on seizure progression, severity, and post-seizure cellular reorganization. In Aim 2, I will assess the extent to which activation of specific serotonergic neuron subtypes can ameliorate or prevent seizures, seizure-induced cellular reorganization, and/or seizure-induced memory deficits. Given the genetic tools, mouse models, and expertise of the lab, along with successful preliminary studies integrating seizure-induction and behavioral and histopathological readouts, the proposed work is feasible. We have as well engaged experts in epilepsy and seizure models and mouse neurobehavioral memory assays, further ensuring expeditious completion and concomitant in depth pre-doctoral training. Results are expected to inform on the basic neurobiology underlying serotonergic protection from seizures and their sequelae. Coupled with our recent extensive molecular characterization of these serotonergic neuron subtypes, findings here could inform development of highly targeted therapeutics for epilepsy.